Type I Interferons (the family of IFNa proteins and IFNp) and Type II IFN (IFNy) play central and essential roles in promoting innate immunity against a wide variety of viruses, bacteria and parasites. The IFNs induce not only cell-intrinsic mechanisms that protect host cells against pathogen infection but also activate a variety of cell-extrinsic mechanisms leading to activation of NK cells, macrophages, polymorphonuclear leukocytes and T cells that destroy infected cells. Our knowledge of IFN biology has stemmed largely from in vitro experiments performed on IFN-responsive versus unresponsive cells and in vivo approaches in which IFN responsiveness is globally ablated in mice through use of neutralizing or blocking monoclonal antibodies or through disruption of genes encoding either the IFN species themselves or their respective receptors. The physiologic relevance of these studies have been validated by the discovery of humans who have distinct defects in either producing or responding to the various forms of IFN. However, since the receptors for IFNa/p or IFNy are expressed on nearly all cells, we still know very little about the cell-specific functions of these cytokines in vivo. Since the IFNs play such a key role in innate immunity, obtaining a more detailed understanding of their common and unique effects on different cell populations is not only needed but essential if we wish to intentionally stimulate innate immunity, either prophylactically or therapeutically, to protect us against naturally-occurring (e.g. pandemic viral infections) or intentionally-produced (e.g., bioterrorism) infections. Armed with (1) an extensive understanding of IFN biology that the Schreiber lab has gained from molecular and genetic experiments conducted over the last 28 years (2) a comprehensive knowledge that exists within the Unanue laboratory about the immunobiology of Listeria monocytogenes infection, and (3) the particularly broad and deep understanding of virology that the other members of this MRCE program bring to this application, we propose to produce and study mice on a stabilized C57BL/6 genetic background that lack responsiveness to IFNa/p or IFNy in specific cell types to define the tissue specific actions of the IFNs to infection with priority pathogens.